Project Summary The cycle of repeated composite-restoration replacements is a pernicious problem?each replacement risks pulpal injury, increased tooth weakness, and eventually, tooth loss. The problem is pervasive?nearly 70% of all composite restorations are replacements and the leading cause of failure is recurrent marginal decay. Unlike amalgam, composite lacks the inherent capability to seal discrepancies at the material/tooth interface. The adhesive that bonds the composite to the tooth is intended to seal the interface, but the adhesive seal to dentin is fragile?it is readily damaged by acids, enzymes, and other oral fluids. Bacteria and bacterial by-products infiltrate the resulting marginal gaps, demineralize and decompose the tooth, and further erode the adhesive, leading to wider and deeper gaps that create an ideal environment for bacteria to proliferate. Biodegradation by- products accumulate at the dentin/adhesive interface and increase the virulence of cariogenic bacteria, provoking a positive feedback loop that escalates the degradation. There is an urgent need to address this composite/tooth-interface vulnerability through multi-factorial approaches that: i) remineralize damaged dentin; ii) inhibit bacterial attack; and iii) provide durable polymers. Recent findings from our lab offer significant promise for meeting this need. First, we have synthesized novel self-strengthening polymers?the self-strengthening mechanism provides a persistent, intrinsic reinforcement of the polymer network in both neutral and acidic conditions. We have engineered antimicrobial and remineralizing peptides and tethered them to self- strengthening-adhesive monomers. Building on our progress, we propose to use both engineered peptides and antibacterial agents tethered to novel polymers to provide a ?bio-hybrid? adhesive that will serve as a durable barrier to recurrent decay. Our threefold strategy exploits: (i) polymer-tethered engineered peptides and antibacterial agents to simultaneously provide antibacterial activity, delay biofilm formation, and remineralize dentin; (ii) self-strengthening polymers that resist hydrolysis-mediated degradation; and (iii) iterative feedback between synthesis, characterization, and modeling to forecast performance under relevant in vivo conditions.